Pentanoic acid derivatives

ABSTRACT

The compound of the formula (I): 
                         
wherein R 1  is alkyl substituted by fluorine(s);
     R 2  is hydroxy, alkoxy, alkoxy substituted by phenyl, NR 3 R 4 ,
 
in which R 3 , R 4  is (i) hydrogen, (ii) alkyl, (iii) phenyl, (iv) phenyl substituted by alkoxy or carboxyl, (v) heterocyclic ring containing nitrogen atom, (vi) alkyl substituted by phenyl, phenyl substituted by alkoxy or carboxyl, heterocyclic ring containing nitrogen atom, (vii) the nitrogen bonded to R 3  and R 4 , taken together a saturated heterocyclic ring or amino acid residues;
 
and non-toxic salts thereof and acid addition salts thereof.
   
     The compounds of the present invention of the formula (I) and the compounds of the formula (X): 
                         
wherein n is 0 or 1,
     R 11  is hydrogen and chlorine,   R 5  is R 7 —CH 2 — or R 8 , or   R 5  and R 11 , taken together is alkylidene;   R 6  is hydroxy, alkoxy, alkoxy substituted by phenyl, NR 9 R 10 ,
 
in which R 9 , R 10  is (i) hydrogen, (ii) alkyl, (iii) phenyl, (iv) phenyl substituted by alkoxy or carboxyl, (v) heterocyclic ring containing nitrogen atom, (vi) alkyl substituted by phenyl, phenyl-substituted by alkoxy or carboxyl, heterocyclic ring containing nitrogen atom, (vii) the nitrogen bonded to R 9  and R 10 , taken together a saturated heterocyclic ring or amino acid residues, R 7  is (i) F—(CH 2 ) m — or F 3 C—CH 2 —, (ii) alkyl substituted by chlorine, (iii) alkyl substituted by alkoxy, cycloalkyl, phenyl, phenoxy;
   R 8  is alkyl, alkenyl, alkoxy, alkylthio, cycloalkyl, phenyl, phenoxy;
 
non-toxic salts and acid addition salts thereof are useful for prevention and/or treatment for neurodegenerarive disease (Alzheimer&#39;s disease etc.) and neuronal dysfunction by stroke or traumic injury (Multiple sclerosis etc.) etc.

This is a Continuation of application Ser. No. 09/661,054, filed Sep.13, 2000 (now abandoned), which is a Divisional of application Ser. No.08/681,482, filed Jul. 23, 1996, (issued as U.S. Pat. No. 6,201,021)which is a File Wrapper Continuation of application Ser. No. 08/252,642,filed Jun. 1, 1994 (now abandoned), the disclosures of which areincorporated herein by reference.

SUMMARY

This invention is related to pentanoic acid derivatives. Moreparticularly, this invention is related to:

(1) pentanoic acid derivatives of the formula (I):

wherein all the symbols are the same meaning as hereafter defined, andnon-toxic salts thereof and acid addition salts thereof,

(2) improving agent of the brain functions containing pentanoic acidderivatives of the formula (I) and non-toxic salts thereof and acidaddition salts thereof as active ingredient,

(3) process for the preparation of pentanoic acid derivatives of theformula (I) and non-toxic salts thereof and acid addition salts thereofand

(4) improving agent of the brain functions containing pentanoic acidderivatives of the formula (X):

wherein all the symbols are the same meaning as hereafter defined, andnon-toxic salts thereof and acid addition salts thereof as activeingredient.

BACKGROUND

The two major structural units that form the brain are neuron and glia.The neuron is composed of a cell body with dendrites. Ramifiedstructures that transmit neuro-information along an axon and thosereceiving impulses via other neurons are the two types of dendritesknown in existence. Neuro-information is conducted from one neuron toanother via transmission across the synapse, a cleft that closelyconnects the dendrites of two communicating neurons.

However, glia is units that complement the functions of these neurons bysupplying nutrients, eliminating catabolites/wastes, maintaining aproper ion equilibrium and performing other related functional roles forneurons to physiologically function normally. The glia encompass varioustypes of cells. There are astrocytes, oligodendrocytes and microglia inthe central nervous system; Schwann's and mantle cells in the peripheralnervous system; and ependymal cells in the ventricular endothelium.

The growth and differentiation of neurons prevail immediately before andafter birth, whereas those of glia persist even after birth. Theetiological factors of neurodegenerative diseases (such as Alzheimer'sdisease, multiple sclerosis, hepatic encephalopathy and delayed neuronaldeath) have been thought to be attributed mainly to abnormalities in theneurons. However, attention has recently been focused on the functionalabnormalities of glia surrounding the neurons, especially astrocytes(Scientific American, pp 45–52, April 1989). This is because astrocytesnot only act as complementary cells, but they also promote themetabolism of glutamate and γ-amino butyrate (GABA), syntheses ofneuropeptides and cytokines, and function as either immunocysts orneurons beside displaying important roles in regulating brain functions.As such, abnormalities in the astrocyte functions may be the determinantfactors in inducing various brain-related diseases.

When encephalopathia occurred, reactive astrocytosis generated fromastrocyte-derived reactive astrocytes agglutinate in the vicinity ofsites where neurons die [J. Anat., 106, 471 (1970); Dev. Biol., 72, 381(1979); Adv. Cell. Neurobiol., 2, 249 (1981)]. Although reactiveastrocytosis eventuated in brain insults has been thought to be acompensatory response to neuronal regeneration, recent evidences havesuggested that the excessive response of reactive astrocytosis triggersneurodegenerative decidua [Science, 237, 642 (1987); Brain Res., 481,191 (1989); Ibid, 547, 223 (1991)]. From the participating reactiveastrocytes in this excessive response, various neurotransmitters andcytokines are released [Cytobios., 61, 133 (1990)]. Of these, the mostsignificant have been the identification of nerve growth factor (NGF)[Biochem. Biophys. Res. Commun., 136, 57 (1986); Brain Res., 560, 76(1991)] and β-amyloid precursor protein (β-APP) secretions [Neuron., 3,275 (1988); J. Neurosci. Res., 25, 431 (1990); FEBS Lett., 292, 171(1991)]. The expression of β-APP has prompted reactive astrocytes as apossible source of β-amyloid, and the close relationship betweenβ-amyloid deposits and reactive astrocytosis has since been implicated[J. Neurol. Sci., 112, 68 (1992)]. β-amyloid plagues display animportant role in the induction of Alzheimer's disease (AD), arepresentative neurodegenerative disease [Proc. Natl. Acad. Sci. USA.,82, 4245 (1985); Brain Res. Reviews, 16, 83 (1991); TIPS, 12, 383(1991)].

Base on the dose/efficacy relationship, NGF secreted from the reactiveastrocytes elicits a neurotoxic activity 1.0×10⁵-fold more potent thanthat of β-amyloid alone [Science, 250, 279 (1990)], and indicates asynergistic effect on β-amyloid-induced neuronal death [Proc. Natl.Acad. Sci. USA, 87, 9020 (1990)]. Furthermore β-amyloid also facilitatesneuronal deaths induced by excitatory amino acids such as glutamate andN-methyl-D-aspartate (NMDA) [Brain Res., 533, 315 (1990)]. As such,these facts may be able to account for the pathological findings relatedto β-amyloid in AD.

Recent finding have implicated that abnormalities in the astrocytefunctions are found in AD patients. In addition, reactive astrocyteshave been postulated to relate directly to AD induction [Neurol., 40, 33(1990); Neurobiol. Aging, 13, 239 (1992)].

However, it is still unclear as to why reactive astrocytosis would occursuperfluously. The present inventors therefore studied the inductions ofreactive astrocytes so as to define the physiological functions of thisendogenous element using primary cultured astrocytes from neonatal ratbrains. By culturing astrocytes from physically destroyed brains bynormal culture procedure, the reactive astrocytes were successfullyinduced. Consequently, in addition to a remarkably abnormal cellproliferation initiated on 5 days in vitro (DIV), enhanced glialfibrillary acidic protein (GFAP) contents and specific morphologicalchanges (hyperplasia) in the reactive astrocytes were also observed.

After establishing and confirming the above findings, the functionalchanges which occurred during the induction of reactive astrocytes werepursued. The results did not revealed any significant changes in thevoltage-dependent calcium, sodium and potassium channels and glutamatereceptor responses in reactive astrocytes. However, a disappearance ofGABA_(A) receptor responses as inhibitory regulation was accompanied bythe attenuated abnormal proliferation of astrocytes in cultures. Theresponse decreased to such an extent that the astrocyte growth wasrendered undetectable. Based on the observation that no receptorresponses to glycine (an inhibitory amino acid) were elicited, reactiveastrocytes were probably induced by a decrease in the inhibitory controlof astrocytes.

All in all, when encephalopathy occurred, a disappearance of GABA_(A)receptor responses of astrocytes ensued. Because astrocytes persistedabnormally, a typical levels of neurotransmitters and cytokines(especially NGF and β-APP) were released. These extraordinary eventsthen produced synergistic effects that eventually induced abnormalramifications/extension of neuronal dendrites followed by neuronaldeath. In other words, sideration of neurodegenerative diseases ensued.

Hence, treatment and/or prevention of neurodegenerative diseasesattributed to functional abnormalities can be innovated and designed byimproving the GABAA receptor responses of reactive astrocytes.

Furthermore, excessive glutamate and aspartate released at the terminalsof ischemic neurons in brain insults cause persistent depolarizationthat eventually neutralizes the neurons concerned [Nikkei Sci J., 9, 52(1991)]. This event is then followed by excessive brain edema andencephalophyma (or astrocytosis), which in turn is ensued by death. Asneurotoxic activities induced by the excessive response of reactiveastrocytes are suppressed, GABA_(A) receptor responses of astrocytes areimproved. These events thus reduce not only the ischemia-inducedmortality cases but can also alleviate/treat the post-ischemia braindysfunction.

RELATED ARTS

Hitherto, drugs that improve a disappearance of GABA_(A) receptorresponses have not been discovered.

PURPOSE OF INVENTION

Based on findings on the excessive response of reactive astrocytes wereinduced by lack of inhibitory control ability of astrocytes, the presentinventors attempted to improve the functional activities of suchastrocytes by using various synthesized inhibitory compounds. Asresults, the present inventors have found that pentanoic acidderivative(s) were potentially useful in improving the GABA_(A) receptorresponses and have accomplished the present invention.

Comparison with the Related Arts

The compound of the present invention of the formula (I) and non-toxicsalts thereof and acid addition salts thereof are all novel compounds.

In the compound of the formula (X), 2-propylpentanoic acid,2-propylpentanamide, 2-propylhexanoic acid, 2-propylheptanoic acid,2-propyloctanoic acid, 2-propylnonanoic acid, 2-propyldecanoic acid,5-methyl-2-propylhexanoic acid, 2-cyclohexylpentanoic acid, methyl2-cyclohexylpentanoate, ethyl 2-cyclohexylpentanoate,2-(2-cyclohexylethyl)pentanoic acid, 2-(3-cyclohexylpropyl)pentanoicacid, 7-fluoro-2-propylheptanoic acid, 8-fluoro-2-propyloctanoic acid,9-fluoro-2-propylnonanoic acid, 5,5,5-trifluoro-2-propylpentanoic acid,2-chloro-2-propylpentanoic acid, 2-propyl-2-pentenoic acid,2-propyl-3-pentenoic acid, 2-propyl-4-pentenoic acid, 2-ethylpentanoicacid and 2-ethylhexanoic acid are already known.

For example, 2-propylpentanoic acid is known as valproic acid and2-propylpentanamide is known as valpromide which already used asantiepileptic. 2-Propyl-2-pentenoic acid, 2-propyl-3-pentenoic acid and2-propyl-4-pentenoic acid are known as metabolites of valproic acid and2-ethylpentanoic acid, 2-ethylhexanoic acid and 2-propylhexanoic acidare known as analogues of valproric acid [Neuropharmacology, 24(5).427–435(1985)]. 5,5,5-Trifluoro-2-propylpentanoic acid is disclosed asantiepileptic in Japanese Kokai Koho 6-116200. The following compoundsare known in Chemical Abstracts Service, but they are not used aspharmaceuticals. Registry Number is described in parentheses.

-   2-propylheptanoic acid (31080-39-4),-   2-propyloctanoic acid (31080-41-8),-   2-propylnonanoic acid (65185-82-2),-   2-propyldecanoic acid (123790-07-8),-   5-methyl-2-propylhexanoic acid (94072-28-3),-   2-cyclohexylpentanoic acid (106854-67-5),-   methyl 2-cyclohexylpentanoate (102617-56-1),-   ethyl 2-cyclohexylpentanoate (22579-21-1),-   2-(2-cyclohexylethyl)pentanoic acid (28396-40-9),-   2-(3-cyclohexylpropyl)pentanoic acid (15331-26-7),-   7-fluoro-2-propylheptanoic acid (6863-43-0),-   8-fluoro-2-propyloctanoic acid (3847-39-0),-   9-fluoro-2-propylnonanoic acid (3847-35-6),-   2-chloro-2-propylpentanoic acid (143100-15-6).    And 2-propyloctanoic acid and 2-propylnonanoic acid are already on    the market as reagents.

Activities of valproic acid for astrocyte are known as follows untilnow.

(1) Inhibition of γ-aminobutylic-acid amino transferase (GABA-T)[Neuropharmacology, 25, 617 (1986)].

(2) Inducing of expression of glia heat shock protein as collagen typeIV receptor [Brain Res., 459, 131 (1988)].

(3) Suppression of increase of glia [Brain Res., 554, 223 (1991)].

(4) Decreasing of affinity for taking in GABA [Neurochem. Res., 17, 327(1992)].

Inhibition of inducing of reactive astrocyte which is discovered by thepresent inventors, is not known at all.

It is not able to expect at all that valproic acid has an inhibitoryactivity of inducing of reactive astrocyte from the above knownactivity. Further, it is the first discovery that the compounds of theformula (X), including 2-propylhexanoic acid, 2-propylheptanoic acid,2-propyloctanoic acid, 2-propylnonanoic acid, 2-propyldecanoic acid,5-methyl-2-propylhexanoic acid, 2-cyclohexylpentanoic acid, methyl2-cyclohexylpentanoate, ethyl 2-cyclohexylpentanoate,2-(2-cyclohexylethyl)pentanoic acid, 2-(3-cyclohexylpropyl)pentanoicacid, 7-fluoro-2-propylheptanoic acid, 8-fluoro-2-propyloctanoic acid,9-fluoro-2-propylnonanoic acid, 5,5, 5-trifluoro-2-propylpentanoic acid,2-chloro-2-propylpentanoic acid and 2-propyl-2-pentenoic acid, have aninhibitory activity of inducing of reactive astrocyte.

DISCLOSURE OF THE INVENTION

The present invention is related to novel compounds, process for thepreparation of the novel compounds, a use of the novel compounds and anovel use of known compounds.

Accordingly, the present invention is related to

-   1) the compound of the formula (I):

wherein R¹ is C1–10 alkyl having one carbon substituted by 1–3 offluorine(s);

-   R² is hydroxy, C1–4 alkoxy, C1–4 alkoxy substituted by 1 of phenyl,    or NR³R⁴,-   in which R³ and R⁴ each, independently, is-   (i) hydrogen,-   (ii) C1–4 alkyl,-   (iii) phenyl,-   (iv) phenyl substituted by C1–4 alkoxy or carboxyl,-   (v) 4–7 membered heterocyclic ring containing one nitrogen or-   (vi) C1–4 alkyl substituted by phenyl, phenyl substituted by C1–4    alkoxy or carboxyl, or 4–7 membered heterocyclic ring containing one    nitrogen, or the nitrogen atom bonded to them, taken together is 4–7    membered saturated heterocyclic ring containing one or two    nitrogen(s) or one nitrogen and one oxygen, or amino acid residue;    with the proviso that, R¹ is not F—(CH₂)₄—, F—(CH₂)₅—, F—(CH₂)₆—,    F₃C—CH₂—; and non-toxic salts thereof and acid addition salts    thereof,-   2) improving agent of the brain functions containing the compound of    the formula (I), non-toxic salts thereof and acid addition salts    thereof as active ingredient,-   3) process for the preparation of the compound of the formula (I),    non-toxic salts thereof and acid addition salts thereof,-   4) improving agent of the brain functions containing the compound of    the formula (X):

wherein n is 0 or 1;

-   R¹¹ is hydrogen or chlorine;-   R⁵ is R⁷—CH₂— or R⁸, or-   R⁵ and R¹¹, taken together is C3–10 alkylidene;-   R⁷ is F—(CH₂)_(m)—, in which m is 4–6,-   F₃C—CH₂—, C2–10 alkyl substituted by 1 or 2 of chlorine(s), or C1–5    alkyl substituted by 1 or 2 of C1–4 alkoxy, C3–7 cycloalkyl, phenyl    or phenoxy;-   R⁸ is (i) C3–10 alkyl-   (ii) C3–10 alkenyl,-   (iii) C2–10 alkoxy,-   (iv) C2–10 alkylthio,-   (v) C3–7 cycloalkyl,-   (vi) phenyl or-   (vii) phenoxy;-   R⁶ is hydroxy, C1–4 alkoxy, C1–4 alkoxy substituted by 1 of phenyl,    or NR⁹R¹⁰,    in which R⁹ and R¹⁰ each, independently, is-   (i) hydrogen,-   (ii) C1–4 alkyl,-   (iii) phenyl,-   (iv) phenyl substituted by C1–4 alkoxy or carboxyl,-   (v) 4–7 membered heterocyclic ring containing one nitrogen or-   (vi) C1–4 alkyl substituted by phenyl, phenyl substituted by C1–4    alkoxy or carboxyl, or 4–7 membered heterocyclic ring containing one    nitrogen, or the nitrogen atom bonded to them, taken together is 4–7    membered saturated heterocyclic ring containing one or two    nitrogen(s) or one nitrogen and one oxygen, or amino acid residue;    non-toxic salts thereof and acid addition salts thereof.

In the formula (I), C1–10 alkyl having one carbon substituent by 1–3 offluorine(s) represented by R¹ means methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomeric groups thereofhaving one carbon substituted by 1, 2 or 3 of fluorine(s) and all groupsare preferable. Especially preferable group is C1–7 alkyl having onecarbon substituent by 1–3 of fluorine(s).

C1–4 alkoxy represented by R², R⁶ or C1–4 alkoxy as a substituent ofphenyl in R³, R⁴, R⁹ or R¹⁰ means methoxy, ethoxy, propoxy, butoxy andisomeric groups thereof and all groups are preferable. It's alsopreferable that R² or R⁶ is hydroxyl.

C1–4 alkyl represented by R³, R⁴, R⁹ or R¹⁰ means methyl ethyl, propyl,butyl and isomeric groups thereof.

4–7 membered heterocyclic ring containing one nitrogen represented byR³, R⁴, R⁹ or R¹⁰ means pyrrole, pyridine, azepine or partiallysaturated rings thereof or all saturated rings (pyrrolidine, piperidineetc.) and all rings are preferable. Especially preferable ring ispyridine.

4–7 membered saturated heterocyclic ring containing one nitrogenrepresented by R³, R⁴ and the nitrogen atom bonded to them, or R⁹, R¹⁰and nitrogen atom bonded to them means azetidine, pyrrolidine,piperidine or perhydroazepine and all rings are preferable. Especiallypreferable ring is piperidine.

4–7 membered saturated heterocyclic ring containing two nitrogensrepresented by R³, R⁴ and the nitrogen atom bonded to them, or R⁹, R¹⁰and nitrogen atom bonded to them means pyrazolidine, imidazolidine,perhydrodiazine (piperazine etc.) perhydrodiazepine and all rings arepreferable. Especially preferable ring is piperazine.

4–7 membered saturated heterocyclic ring containing one nitrogen and oneoxygen represented by R³, R⁴ and the nitrogen atom bonded to them, orR⁹, R¹⁰ and nitrogen atom bonded to them means oxazolidine,perhydroxazine (morpholine etc.) perhydroxazepine and all rings arepreferable. Especially preferable ring is morpholine.

The amino acid residue which is constituted by R³, R⁴ and the nitrogenatom bonded to them, or R⁹, R¹⁰ and nitrogen atom bonded to them meansany amino acid residue. The amino acid residue may also includes theesters which is converted the carboxyl part of it. For example, they areglycine, alanine, serine, cysteine, cystine, threonine, valine,methionine, leucine, isoleucine, norleucine, phenylalanine, tyrosine,thyronine, proline, hydroxyproline, tryptophane, aspartic acid, glutamicacid, arginine, lysine, ornithine, histidine residue or ester (C1–4alkyl ester or benzyl ester) thereof. Especially preferable amino acidis glycine.

C2–10 alkyl represented by R⁷ means ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl and isomeric groups thereof and C1–5 alkylrepresented by R⁷ means ethyl, propyl, butyl, pentyl and isomeric groupsthereof.

C1–4 alkoxy as substituent of C1–5 alkyl in R⁷ means methoxy, ethoxy,propoxy, butoxy and isomeric groups thereof. C3–7 cycloalkyl representedby R⁷ means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

C3–10 alkyl represented by R⁸ means propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl and isomeric groups thereof and all groupsare preferable. Especially preferable group is C3–7 alkyl.

C3–10 alkenyl represented by R⁸ means propenyl, butenyl, pentenyl,hexenyl, heptenyl, octenyl, nonenyl, decenyl and isomeric groups thereofand all groups are preferable. C2–10 alkoxy means ethoxy, propoxy,butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy andisomeric groups thereof and all groups are preferable. C2–10 alkylthiomeans ethylthio, propylthio, butylthio, pentylthio, hexylthio,heptylthio, octylthio, nonylthio, decylthio and isomeric groups thereofand all groups are preferable. C3–7 cycloalkyl means cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and all groups arepreferable.

C3–10 alkylidene represented by R⁵ and R¹¹, taken together meanspropylidene, butylidene, pentylidene, hexylidene, heptylidene,octylidene, nonylidene, decylidene and isomeric groups thereof and allgroups are preferable.

Preferable Compounds

In the compounds of the present invention of the formula (I), thecompounds described in Example and the following compounds arepreferable.

(1)

R¹ FH₂C—(CH₂)₆— FH₂C—(CH₂)₇— FH₂C—(CH₂)₈— FH₂C—(CH₂)₉— F₂HC—(CH₂)₆—F₂HC—(CH₂)₇— F₂HC—(CH₂)₈— F₂HC—(CH₂)₉— F₃C—(CH₂)₆— F₃C—(CH₂)₇—F₃C—(CH₂)₈— F₃C—(CH₂)₉— (2)

R¹ R² FH₂C—(CH₂)₂— —NH₂ ″ —NHC₂H₅ ″ —N(CH₃)₂ ″

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R¹ R² F₂HC—(CH₂)₄— —NH₂ ″ —NHC₂H₅ ″ —N(CH₃)₂ ″

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In the compounds of the present invention of the formula (X), thecompounds described in Example and the following compounds arepreferable.

(1)

n R¹¹ R⁵ 0 H FH₂C—(CH₂)₄— 0 H FH₂C—(CH₂)₅— 0 H FH₂C—(CH₂)₆— 0 H(H₃C)₂HC—(CH₂)₂— 0 H (H₃C)₂HC—(CH₂)₃— 0 H (H₃C)₂HC—(CH₂)₄— 0 HH₃C—(CH₂)₄—O— 0 H H₃CO—(CH₂)₄— 0 H

0 H H₃C—(CH₂)₂— 0 H H₃C—(CH₂)₅— 0 H H₃C—(CH₂)₆— 0 Cl H₃C—(CH₂)₂— 0 ClH₃C—(CH₂)₅— 0 Cl H₃C—(CH₂)₆— 1 Cl FH₂C—(CH₂)₄— 1 Cl FH₂C—(CH₂)₅— 1 ClFH₂C—(CH₂)₆— 1 Cl (H₃C)₂HC—(CH₂)₂— 1 Cl (H₃C)₂HC—(CH₂)₃— 1 Cl(H₃C)₂HC—(CH₂)₄— 1 Cl H₃C—(CH₂)₄—O— 1 Cl H₃CO—(CH₂)₄— 1 Cl

1 Cl H₃C—(CH₂)₂— 1 Cl H₃C—(CH₂)₅— 1 Cl H₃C—(CH₂)₆— 1 H H₃C—(CH₂)₄—CH═ 1H H₃C—(CH₂)₅—CH═ H₃C—CH═CH— 1 H H₂C═CH—(CH₂)₅— 1 H H₃C—(CH₂)₂— 1 HH₃C—(CH₂)₆— (2)

R⁵ R⁶ H₃C—(CH₂)₂—

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H₃C—(CH₂)₅— —N(CH₃)₂ ″

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H₃C—(CH₂)₆—

″ —NH₂ ″ —NHCH₃ ″

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FH₂C—(CH₂)₄—

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FH₂C—(CH₂)₆—

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F₃C—CH₂— —NH₂ ″ —NHC₂H₅ ″ —N(CH₃)₂ ″

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In the present invention, it is able to formulate using each activeingredient or combination of more than two active ingredients.

Unless otherwise specified, all isomers are included in the invention.For example, alkyl, alkoxy and alkenyl includes straight and branchedones. Double bond in alkenyl includes E, Z and EZ mixture. Isomersgenerated by asymmetric carbon(s) e.g. branched alkyl are included inthe present invention.

Salts

The compounds which R² is hydroxyl among the compounds of the formula(I) or R⁶ is hydroxyl among the compounds of the formula (X), of thepresent invention may be converted into the corresponding salts.Non-toxic and water-soluble salts are preferable. Suitable salts, forexample, are as follows:

-   salts of alkaline metal (sodium, potassium etc.), salts of alkaline    earth metal (calcium, magnesium etc.), ammonium salts, salts of    pharmaceutically acceptable organic amine (tetramethylammonium,    triethylamine, methylamine, dimethylamine, cyclopentylamine,    benzylamine, phenethylamine, piperidine, monoethanolamine,    diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine,    N-methyl-D-glucamine etc.).    Acid Addition Salts

The compounds of the formula (I) and (X) may be converted into thecorresponding acid addition salts. Non-toxic and water-soluble salts arepreferable. Suitable salts, for example, are as follows:

-   salts of inorganic acids e.g. hydrochloride, hydrobromide,    hydroiode, sulfate, phosphate, nitrate; salts of organic acids e.g.    acetate, lactate, tartarate, benzoate, citrate, methanesulphonate,    ethanesulphonate, benzenesulphonate, toluenesulphonate, isedthioate,    glucuronate, gluconate.    Process for the Preparation

The compounds of the present invention of the formula (I), may beprepared:

(i) by subjecting a compound of the formula (II):

wherein R^(1a) is C1–10 alkyl having one carbon substituted by 1 or 2 offluorine(s) and R^(2a) is C1–4 alkoxy;or the compound of the formula (V):

wherein R^(1d) is C1–10 alkyl having one carbon substituted by 3 offluorines and R^(2a) is the same meaning as hereinbefore defined;or the compound of the formula (VIII):

wherein R^(1f) is C1–10 alkyl having one carbon substituted by 3 offluorines and R^(2a) is the same meaning as hereinbefore defined;to hydrogenation,

(ii) by hydrolysis of ester in an alkaline condition of the compound ofthe formula (I-a):

wherein all the symbols are the same meaning as hereinbefore defined,

(iii) by reacting of the acyl chloride compound of the formula (I-b):

wherein R¹ is the same meaning as hereinbefore defined;

(iii-1) with a compound of the formula (A):HNR³R⁴  (A)wherein R³ and R⁴ are the same meaning as hereinbefore defined; or

(iii-2) with a compound of the formula (H):R^(2b)—OH  (H)wherein R^(2b) is C1–4 alkyl substituted by 1 of phenyl.

And the compound which NR³R⁴ is the amino acid residue containingunesterfied carboxyl group in the formula (I), may be prepared bysubjecting the compound which NR³R⁴ is the amino acid wherein carboxylgroup is esterfied by benzyl in the formula (I–C):

wherein all symbols are the same meaning as hereinbefore defined;obtained by reaction (iii-1), to hydrogenation.

The compounds of the formula (II), (V), (VIII), (I-a) and (I-b) may beprepared by using a reaction depicted in following Scheme (A-1) and(A-2).

In the scheme, R^(1b) is C1–10 alkyl having one carbon substituted byone ketone, R^(1c) is C1–10 alkyl having one carbon substituted by onehydroxyl, R^(1e) is C1–10 alkyl having one carbon substituted by onehydroxyl or three fluorines, X is mesylate, tosylate or halogen atoms,and the other symbols are the same meaning as hereinbefore defined. DASTis diethylaminosulfure trifluoride, LDA is lithium diisopropylamide, DBUis 1,8-diazabicyclo[5.4.0]undec-7-ene.

The hydrogenation of the reaction (i) is known, for example, it may becarried out in an organic solvent (tetrahydrofuran (THF), dioxane,diethylether, ethyl acetate, methanol, ethanol, etc.) using a catalyst(palladium on carbon, palladium, hydroxy palladium, palladium aceticacid, palladium black, platinum black, nickel, Ranney nickel, etc.) atnormal or elevated pressure of hydrogen gas, at 0–80° C.

The hydrolysis of ester in an alkaline condition of the reaction (ii) isknown, for example, it may be carried out in water miscible organicsolvent (THF, dioxane, ethanol, methanol, dimethoxyethane or two or moreof the mixture, etc.) using an aqueous solution of an alkaline(potassium hydroxide, sodium hydroxide, etc.) at −10–100° C.

The amidation of the reaction (iii-1) is known, for example, it may becarried out with oxalyl chloride, and then by reacting a compound thusobtained with an amine of the formula NR³R⁴, wherein R³ and R⁴ are thesame meaning as hereinbefore defined, in an inert organic solvent (THF,methylene chloride, toluene, diethylether, etc.), in the presence orabsence of an appropriate base (triethylamine, etc.) at 0–40° C.

And, the hydrogenation is the same process as hereinbefore defined.

The reaction (iii-2) is known, for example, it may be carried out withoxalyl chloride, and then by reacting a compound thus obtained with analcohol of the formula R^(2b)—OH, wherein R^(2b) is the same meaning ashereinbefore defined, in an inert organic solvent (THF, methylenechloride, toluene, diethylether, etc.), in the presence or absence of anappropriate base (triethylamine, etc.) at 0–40° C.

The compounds of the formula (X) in the present invention, may beprepared:

(i) by subjecting a compound of the formula (XI):

wherein R^(7a) is F—(CH₂)_(m)—, in which m is 4–6, R^(6a) is C1–4 alkoxyand n is the same meaning as hereinbefore defined;or the compound of the formula (XIII):

wherein R^(7c) is F₃C—CH₂—, C2–10 alkyl substituted by 1 or 2 ofchlorine(s), or C1–5 alkyl substituted by 1 or 2 of C1–4 alkyl, C3–7cycloalkyl, phenyl or phenoxy, and R^(6a) and n are the same meaning ashereinbefore defined;to hydrogenation,

(ii) by subjecting a compound of the formula (XVI):

wherein R^(8a) is C3–10 alkyl and the other symbols are the same meaningas hereinbefore defined;to hydrogenation,

(iii) by reacting a compound of the formula (XVIII):

wherein all the symbols are the same meaning as hereinbefore defined;with the formula (D):R^(8b)—Br  (D)wherein R^(8b) is C3–10 alkenyl; orwith the formula (E):(R^(8c)—S)₂  (E)wherein R^(8c) is C2–10 alkyl,

(iv) by reacting a compound of the formula (XIX):

wherein all the symbols are the same meaning as hereinbefore defined;with the formula (F):R^(8d)—I  (F)wherein R^(8d) is C2–10 alkyl,

(v) by reacting a compound of the formula (XX):

wherein R^(8e) is phenyl, phenoxy or C3–7 cycloalkyl and R^(6a) is thesame meaning as hereinbefore defined;with the formula (G):

wherein n is the same meaning as hereinbefore defined;

(vi) by subjecting a compound of the formula (XXI):

wherein R^(8f) is C2–9 alkyl, X is mesylate, tosylate or halogen atomsand R^(6a) and n are the same meaning as hereinbefore defined;to elimination reaction,

(vii) by reacting a compound of the formula (X-a):

wherein all the symbols are the same meaning as hereinbefore defined;with carbon tetrachloride,

(viii) by subjecting a compound of the formula (X-d):

wherein all the symbols are the same meaning as hereinbefore defined; toreduction reaction and oxidation reaction,

(ix) by hydrolysis of ester in an alkaline condition of the compound ofthe formula (X-a):

wherein all the symbols are the same meaning as hereinbefore defined;

(x) by reacting of the acyl chloride compound of the formula (X-b):

wherein all the symbols are the same meaning as hereinbefore defined;

(x-1) with a compound of the formula (B):HNR⁹R¹⁰  (B)wherein R⁹ and R¹⁰ are the same meaning as hereinbefore defined; or

(x-2) with a compound of the formula (J):R^(6b)—OH  (J)wherein R^(6b) is C1–4 alkyl substituted by 1 of phenyl.

And the compound which NR⁹R¹⁰ is the amino acid residue containingunesterfied carboxyl group in the formula (X), may be prepared bysubjecting the compound which NR⁹R¹⁰ is the amino acid wherein carboxylgroup is esterfied by benzyl in the formula (X-C):

wherein all the symbols are the same meaning as hereinbefore defined;obtained by reaction (x-1), to hydrogenation.

The compounds of the formula (XI), (XIII), (XVI), (XXI), (X-a), (X-b)and (X-d) may be prepared by using a reaction depicted in followingScheme (B-1), (B-2) and (B-3).

In the scheme, R^(7b) is HO—(CH₂)_(n)—, wherein n is the same meaning ashereinbefore defined, R^(7d) is HO—(CH2)_(n)—, wherein n is the samemeaning as hereinbefore defined, or F₃C—CH₂—, or C2–10 alkyl substitutedby 1 or 2 of chlorine(s), or C1–5 alkyl substituted by 1 or 2 of C1–4alkoxy, C3–7 cycloalkyl, phenyl or phenoxy, and the other symbols arethe same meaning as hereinbefore defined. DAST and LDA are the samemeaning as hereinbefore defined, LAH is lithium aluminum hydride, PDC ispyridinium dichromate.

In each reaction in the present specification, products may be purifiedby conventional manner. For example, it may be carried out bydistillation at atmospheric or reduced pressure, high performance liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction, or after a seriesof reactions.

Starting Materials and Reagents

The starting materials and reagents in the present invention are knownper se or may be prepared by known methods.

For example, the compound of the formula:

in the compounds of the formula (VII) is on the market.

The compound of the formula:

in the compounds of the formula (XV) is on the market.

The compound of the formula:

in the compounds of the formula (XX) is on the market.

The compound of the formula:

in the compounds of the formula (VI) may be prepared by known methods,for example, using the compound of the formula:

being on the market and triphenylphosphine being on the market.

And process of the preparation of 2-propylpentanoic acid and non-toxicsalts thereof are described in specification of the U.S. Pat. No.4,127,604.

Pharmacological Activities

The compounds of the present invention of the formula (I), the compoundsof the formula (X), non-toxic salts thereof and acid addition salts areuseful for improvement of cerebral function, for in animals includinghuman beings, especially human beings, because they have an activity offunctional improvement of astrocyte and their toxicity is very low. Anobject disease, for example are as follows: Neurodegenerative disease(e.g. Alzheimer's disease, Amyotrophic lateral sclerosis, Progressivesupra nuclear palsy, Olive-ponto-cerebellar atrophy), Neuronaldysfunction by stroke or traumatic injury (e.g. Demyelinative disease(Multiple Sclerosis etc.), Brain tumors (Astrocytoma etc.), Infection(Meningitis, Brain abscess, Creutzfeldt-Jakob disease, AIDS dementiaetc)).

For example, in standard laboratory test, the effects were confirmed asfollows.

Experiment 1: Effects in Improving Astrocyte Functions

[Methods]

Preparation of astrocyte cultures: After removing the meninges, isolatedcerebrum of neonatal rats (age: day 1) were placed on frostedglass-slides and minced. The sample was then digested with trypsin(0.25%) and DNase I (0.02%) and suspended in 10% FCS-DMEM beforecentrifugation. After resuspending in 10% FCS-DMEM, the suspension wasdispersed in dishes and cultured at 37° C. under 5% CO₂ atmosphere.Non-adherent cells were removed from the dishes after agitation/washingon post-culture 24 hours. Note that the adherent cell population wascomposed of more than 95% of GFAP-positive cells.

GFAP contents and GABA_(A) receptor responses: The improvement effectson astrocyte functions were evaluated from the following indices:inhibition derived from the increase in GFAP content and inhibition inthe disappearance of GABA_(A) receptor responses. Thus, sodium valproate(Sigma Chem. Co., U.S.A.) was added on 1 DIV followed by whole-cell modevoltage-clamp method on 7 DIV to measure the GABA (3×10⁻⁵ M)-induced Cl⁻current. The Cl⁻ current was taken as an index for the GABA response.Furthermore, GFAP contents were determined by the ELISA method on 11DIV.

[Results]

The results are shown in the Table 1. The GFAP contents were expressedas a ratio of the control group.

TABLE 1 The improvement effects on astrocyte functions Ratio of increaseGABA_(A) receptor Concentration in GFAP contents responses Compound (mM)(%) (pA; means ± S.E.) control 100.0 90 ± 43 VPA* 0.3 30.6 254 ± 106 1.036.3 432 ± 98  3.0 44.3 1301 ± 156  *VPA: sodium valproate

From Table 1, sodium valproate reversed the decreases in the GABA_(A)receptor response, and the GFAP contents (index for reactive astrocytes)were remarkably suppressed.

Based on these findings, sodium valproate elicited potent effects inimproving the astrocyte functions.

Experiment 2: Regeneration Effects of GABA_(A) Receptor ResponsesAgainst Reactive Astrocytes.

[Methods]

Astrocytes were prepared and cultured in a manner similar toExperiment 1. On 14 DIV, reactive astrocytes were subjected to a serialpassage (10⁵ cells/dish). The thus adherent reactive astrocytes werewashed, and transferred to culture media containing the presenteffectively developed compound(s) or invention. On 14 DIV after serialpassages, GABA_(A) receptor responses were tested according toprocedures designated in Experiment 1.

[Results]

The results are shown in Table 2 and 3.

TABLE 2 GABA_(A) receptor Concentration responses Ex. No. (mM) (pA;means ± S.E.) control 8 ± 6 2 0.3 193 ± 103 1.0 628 ± 227 2(2) 0.1 114 ±81  0.3 527 ± 201 2(5) 3.0 326 ± 148 2(6) 0.3 184.0 ± 118.1 3.0 528.0 ±160.2 2(8) 1.0 470.6 ± 124.9 3.0 808.6 ± 325.4 2(9) 0.3 236.4 ± 85.5 2(10) 0.3 800.0 ± 415.6 2(12) 1.0 672 ± 242 3.0 1109 ± 227 

TABLE 3 GABA_(A) receptor Concentration responses Ex. No. (mM) (pA;means ± S.E.) control 8 ± 6 VPA* 0.3 37 ± 26 1.0 193 ± 141 3.0 1263 ±303  7 0.3 213.1 ± 150.1 1.0 661.7 ± 306.3 7(1) 0.3 260.0 ± 47.3  7(2)0.3 730.0 ± 226.4 7(4) 0.3 163.0 ± 60.4  7(8) 1.0 59.0 ± 20.6 7(9) 0.3512.1 ± 233.1 3.0 226.3 ± 60.5  7(14) 3.0 285.7 ± 103.6 7(16) 0.3 105 ±65  1.0 417 ± 140 7(17) 0.3 259.0 ± 83.7  7(18) 1.0 658.6 ± 440.7 7(26)3.0 344.7 ± 342.5 7(28) 3.0 122 ± 44  7(30) 0.3 233 ± 90  1.0 675 ± 2017(31) 0.3 51 ± 28 1.0 565 ± 278 3.0 590 ± 180 7(32) 0.1 48 ± 20 7(33) 0.03 40 ± 23 0.1 237 ± 69  0.3 1260 ± 521  7(37) 0.3 139 ± 52  3.0 595± 190  9 3.0 467 ± 187 11 0.3 35 ± 15 1.0 190 ± 134 3.0 281 ± 174 13 3.0171 ± 55  2-PNA**  0.03 85 ± 41 0.1 107 ± 50  0.3 380 ± 124 *VPA: sodiumvalproate **2-PNA: 2-propylnonanic acid

From Table 2 and 3, each active ingredient elicited marked regenerationeffects on the loss of GABA_(A) receptor responses. This findingindicated that the relevant compounds under investigation were effectivein transforming reactive astrocytes to astrocytes.

Experiment 3: Suppressive Effects on Cell Death in the SymbioticNeurons-Astrocytes Co-Culture System.

[Methods]

Astrocytes, prepared in a manner similar to that of Experiment 1, werecultured for 14 days. Previously prepared neurons (3×10⁴ cells/well),isolated from cerebrum of 19-day old fetus rats, were added to thecultured astrocytes (3×10⁵ cells/well) and allowed to grow. During theculture process, survival rates and neuronal dendriteextension/ramification of neurons were observed. Note that, sodiumvalproate (3 mM) and astrocytes were initially added to the neuronsconcomitantly, and freshly prepared similar culture media containing theinvented compound (3 mM) were subsequently added at 3˜4-day intervals.

[Results]

The results are shown in Table 4.

TABLE 4 Suppressive effects on neuron death Survival rates Compound (on22 days) control <10% VPA 60–70% VPA: sodium valproate

Almost all neurons in the control group died out, and dendritegeneration was not observed. However, marked survival rates and dendritegeneration in the neurons were detected in the sodium valproate-treatedcultures.

Experiment 4: Effects on Experimental Brain Ischemia

[Methods]

Establishing the experimental brain ischemia model: Vertebral arteriesof pentobarbital-anesthetized rats were bilaterally coagulated, and aperiod of 7 days was allowed for recovery. The previously surgicallyexposed bilateral common carotid arteries of ischemic rats weremechanically ligated for 20 min. Immediately after deligation, the ratswere once daily injected i.p. with sodium valproate (300 mg/kg) for 4consecutive days. On deligation day 5˜6, mobility aspects in theconditional avoidance experiment were monitored.

Mobility aspects of the conditional avoidance experiment: The step-upmodel of the dark/light box was used. Animals placed in the dark sectionof the grid-floored box with the connecting door closed were allowed toaccustomed to the environment for 1 minute. The door was then opened for10 seconds. Rats that stepped up to the lighted section via the openeddoor were considered positive in the conditional avoidance test. Animalscategorized as negative in the test were placed in the dark section withthe door closed for 10 seconds prior to subjecting them to electric footshock at 2 mA for 50 seconds. Those rats that did not mobilize to thelighted section of the box by the electric shock were omitted from thetest. The above procedure was repeated 5 trials per day at 30-minutesintervals. A total of 10 trials within 2 days were attempted.

[Results]

The data are illustrated in FIG. 1. Compared to the ischemic referencegroup (2.8±0.8), the normal and sham-operated groups scored frequenciesof 6.1±0.7 and 4.8±0.8, respectively. However, a count of 5.3±0.8 wasregistered in the sodium valproate-treated group, clarifying thatmobility impairment of the learned conditional avoidance responseinduced by recirculation of the ischemic brain was improved by theinvented compound(s).

Toxicity

The toxicity of each active ingredient in the present invention andnon-toxic salts thereof and acid addition salts thereof are very low.For example, the acute toxicity (LD₅₀) in mouse of sodium valproate was1700 mg/kg by oral administration (Merck Index, 11, pp 1559). Therefore,each active ingredient in the present invention may be estimated to safefor pharmaceutical use.

Application for Pharmaceuticals

The compounds of the present invention of the formula (I) and thecompounds of the formula (X), non-toxic salts thereof and acid additionsalts thereof, are useful for improvement of cerebral function, becausethey have an activity of functional improvement of astrocyte.

For example, they are expected to be useful for neurodegenerativedisease (e.g. Alzheimer's disease, Amyotrophic lateral sclerosis,Progressive supra nuclear palsy, Olive-ponto-cerebellar atrophy),neuronal dysfunction by stroke or traumatic injury (e.g. Demyelinativedisease (Multiple Sclerosis etc.), Brain tumors (Astrocytoma etc.),Infection (Meningitis, Brain abscess, Creutzfeldt-Jakob disease, AIDSdementia etc)).

For the purpose above described, each active ingredient in the presentinvention, non-toxic salts thereof and acid addition salts thereof maybe normally administered systemically or partially, usually by oral orparenteral administration.

The doses to be administered are determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 1 mg and 1000mg, by oral administration, up to several times per day, and between 100μg and 100 mg, by parenteral administration (preferable intravenousadministration), up to several times per day.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

When administration of the compounds of the present invention, it isused as solid compositions, liquid compositions or other compositionsfor oral administration, as injections, liniments or suppositories etc.for parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders, and granules.

In such compositions, one or more of the active compound(s) is or areadmixed with at least one inert diluent (such as lactose, mannitol,glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.).

The compositions may also comprise, as is normal practice, additionalsubstances other than inert diluents: e.g. lubricating agents (such asmagnesium stearate etc.), disintegrating agents (such as cellulosecalcium glycolate, etc.), stabilizing agents, and assisting agents fordissolving such as glutamic acid, etc.).

The tablets or pills may, if desired, be coated with a film of gastricor enteric material (such as sugar, gelatin, hydroxypropyl cellulose orhydroxypropylmethyl cellulose phthalate, etc.), or be coated with morethan two films. And further, coating may include containment withincapsules of absorbable materials such as gelatin.

Capsules include hard capsules and soft capsules.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, syrups and elixirs. Insuch compositions, one or more of the active compound(s) is or arecontained in inert diluent(s) commonly used in the art (Purified water,ethanol etc.).

Besides inert diluents, such compositions may also comprise adjuvants(such as wetting agents, suspending agents, etc.), sweetening agents,flavouring agents, perfuming agents, and preserving agents.

Other compositions for oral administration included spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s). Spray compositions may comprise additionalsubstances other than inert diluents: e.g. stabilizing agents (sodiumsulfate etc.), isotonic buffer (sodium chloride, sodium citrate, citricacid, etc.). For preparation of such spray compositions, for example,the method described in the U.S. Pat. No. 2,868,691 or 3,095,355 (hereinincorporated in their entireties by reference) may be used.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. Aqueous solutions,suspensions include distilled water for injection and physiological saltsolution. Non-aqueous solutions, suspensions include propylene glycol,polyethylene glycol, vegetable oil such as olive oil, alcohol such asethanol, POLYSORBATE80 (registered trade mark), etc.

Injections may comprise additional other than inert diluents: e.g.preserving agents, wetting agents, emulsifying agents, dispersingagents, stabilizing agent (human serium albumin, lactose), assistingagents such as assisting agents for dissolving (arginine, glutamic acid,asparaginic acid, polyvinylpyrolydone etc.).

They may be sterilized for example, by filtration through abacteria-retaining filter, by incorporation of sterilizing agents in thecompositions or by irradiation. They may also be manufactured in theform of sterile solid compositions by freeze-drying and which may bedissolved in sterile water or some other sterile diluent(s) forinjection immediately before used.

Other compositions for parenteral administration include liquids forexternal use, and endermic liniments, ointment, suppositories for rectaladministration and pessaries for vaginal administration which compriseone or more of the active compound(s) and may be prepared by per seknown methods.

REFERENCE EXAMPLES AND EXAMPLES

The following reference examples and examples illustrate the presentinvention, but not limit the present invention.

The solvents in the parentheses show the developing or eluting solventsand the rations of the solvents used are by volume in chromatographicseparations.

Unless otherwise specified, “NMR” was measured in a methanol-d (CD₃OD)solution and “IR” was measured by the liquid film method respectively.

Reference Example 1

(1-Methoxycarbonyl-1-butylidene)triphenylphosphorane (5.52 g) was addedto a solution of 5-hydroxypentanal (1.00 g) in benzene (15 ml) under anatmosphere of argon. The mixture was stirred for 15 hours at 80° C. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by column on silica gel (hexane:ethyl acetate=3:1) to givethe title compound (1.17 g) having the following physical data.

TLC: Rf 0.42 (hexane:ethyl acetate=2:1)

Reference Example 2

To a solution of the compound obtained in reference example 1 (389 mg)in tetrahydrofuran (5 ml), dimethylsulfoxide (5 ml), triethylamine (3ml) and sulfur trioxide pyridine complex (619 mg), successively, wereadded under an atmosphere of argon. The mixture was stirred for 40minutes at room temperature. The reaction solution was diluted withether, washed with a saturated aqueous solution of ammonium chloride,water and a saturated aqueous solution of sodium chloride, successively,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by column on silica gel (hexane:ethylacetate=7:1) to give the title compound (268 mg) having the followingphysical data.

TLC: Rf 0.55 (hexane ethyl acetate=3:1)

Reference Example 3

A solution of the compound obtained in reference example 2 (268 mg) inanhydrous dichloromethane (2 ml) was dropped to a solution ofdiethylaminosulfur trifluoride (DAST) (393 μl) in anhydrousdichloromethane (2 ml) under an atmosphere of argon at −78° C. Themixture was stirred for 2.5 hours at 0° C. The reaction mixture wasdiluted with ether, washed with water and a saturated aqueous solutionof sodium chloride, successively, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bycolumn on silica gel (hexane:ethyl acetate=20:1) to give the titlecompound (275 mg) having the following physical data.

TLC: Rf 0.49 (hexane:ethyl acetate=10:1)

Reference Example 5

Tetrahydrofuran (THF) (6 ml) was cooled at −78° C. Lithiumdiisopropylamide (LDA) (2.94 ml) was added to the above THF, andstirred. Ethyl 4,4,4-trifluorobutanoate (1.00 g) was added to themixture, and stirred for 20 minutes at −78° C. Propanal (0.47 ml) wasdropped to the mixture, and stirred for 15 minutes at −78° C. Thereaction mixture was acidified by adding 2N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed with waterand a saturated aqueous solution of sodium chloride, successively, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by column on silica gel (hexane:ethylacetate=5:1) to give the title compound (875 mg) having the followingphysical data.

TLC: Rf 0.33 (hexane:ethyl acetate=5:1)

Reference Example 6

The compound obtained in reference example 5 (875 mg) was dissolved intoa mixture solution of dichloromethane (10 ml) and triethylamine (1 ml).The mixture was cooled at 0° C. Methanesulfonyl chloride (0.446 ml) wasdropped to the mixture. The mixture was stirred for 30 minutes at 0° C.The reaction mixture was poured into water, and extracted with ether.The organic layer was washed with water and a saturated aqueous solutionof sodium chloride, successively, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bycolumn on silica gel (hexane:ethyl acetate=10:1) to give the titlecompound (540 mg) having the following physical data.

TLC: Rf 0.33 (hexane:ethyl acetate=2:1)

Reference Example 7

To a solution of the compound obtained in reference example 6 (540 mg)in benzene (6 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1 ml) wasdropped. The mixture was refluxed for 2 hours. The reaction mixture waspoured into water, and extracted with ether. The organic layer waswashed with 2N hydrochloric acid, water and a saturated aqueous solutionof sodium chloride, successively, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bycolumn on silica gel (hexane:ethyl acetate=30:1) to give the titlecompound (335 mg) having the following physical data.

TLC: Rf 0.55 (hexane:ethyl acetate=5:1)

Example 1

To a solution of the compound obtained in reference example 3 (275 mg)in ethanol (3 ml), 10% palladium on carbon (30 mg) was added, under anatmosphere of argon. The mixture was stirred vigorously for 8 hours atroom temperature under an atmosphere of hydrogen. The reaction mixturewas filtered through Celite and the filtration was concentrated underreduced pressure to give the title compound having the followingphysical data.

TLC: Rf 0.62 (hexane:ethyl acetate=10:1)

Example 2

To a solution of the compound obtained in example 1 in ethanol (8 ml),5N aqueous solution of sodium hydroxide (2 ml) was added. The mixturewas stirred for 2 hours at 70° C. The reaction mixture was concentratedunder reduced pressure. The residue was acidified by adding 2Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with water and a saturated aqueous solution of sodiumchloride, successively, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by columnon silica gel (hexane:ethyl acetate=5:1–2:1) to give the compound offree acid (238 mg). To the above compound in ethanol (5 ml), 1N aqueoussolution of sodium hydroxide (1.06 ml) was added. The mixture wasconcentrated under reduced pressure to give the title compound havingthe following physical data.

TLC: Rf 0.21 (hexane:ethyl acetate=5:1);

IR: ν 3392, 2935, 2871, 1557, 1456, 1416, 1318, 1173, 1123, 1058 cm⁻¹;

NMR: δ 5.87 (1H, tt), 2.22 (1H, m), 1.98–1.23 (12H, m), 0.94 (3H, t).

Example 2(1)–2(10)

The following compounds were obtained by the same procedure as a seriesof reaction of reference example 1→reference example 2→reference example3→example 1→example 2 or reference example 1→reference example 3→example1→example 2 or reference example 1→example 1→example 2, using acorresponding aldehyde.

Example 2(1)

TLC: Rf 0.24 (hexane:ethyl acetate=3:1);

IR (KBr): v 3436, 2963, 2937, 2875, 1639, 1558, 1495, 1412, 1326, 1195,1123, 1048, 964, 583 cm⁻¹;

NMR: δ 5.89 (1H, tt), 2.23 (1H, m), 1.2–2.0 (8H, m), 0.95 (3H, t).

Example 2(2)

TLC: Rf 0.01 (hexane:ethyl acetate=10:1);

IR: ν 3366, 2934, 2863, 1557, 1416, 1124, 1032 cm⁻¹;

NMR: δ 5.87 (1H, tt), 2.23 (1H, m), 1.20–2.00 (14H, m), 0.94 (3H, t).

Example 2(3)

TLC: Rf 0.64 (hexane:ethyl acetate=1:1);

IR (KBr): ν 3401, 2874, 1564, 1447, 1417, 1380, 1320, 1182, 1121, 1048,1005, 835, 755, 559, 427 cm⁻¹;

NMR: δ 5.87 (1H, tt), 2.24 (1H, m), 1.20–2.00 (10H, m), 0.95 (3H, t).

Example 2(4)

TLC: Rf 0.55 (hexane ethyl acetate=2:1);

IR: ν 3368, 2932, 2860, 1556, 1445, 1418, 1124, 1039, 859, 727 cm⁻¹;

NMR: δ 5.87 (1H, tt), 2.22 (1H, m), 1.20–2.00 (16H, m), 0.94 (3H, t).

Example 2(5)

TLC: Rf 0.41 (hexane:ethyl acetate=2:1);

IR (KBr): ν 3651, 3436, 2961, 2936, 2874, 1640, 1553, 1458, 1412, 1322,1113, 1021, 935, 563 cm⁻¹;

NMR: δ 4.40 (2H, dtd), 2.21 (1H, m), 1.25–1.85 (8H, m), 0.91 (3H, t).

Example 2(6)

TLC: Rf 0.61 (hexane:ethyl acetate=1:1)

IR (KBr): ν 3402, 2935, 2873, 1561, 1459, 1415, 1321, 1112, 1037, 750,560 cm⁻¹;

NMR: δ 4.43 (2H, td), 2.23 (1H, m), 1.20–1.90 (10H, m), 0.95 (3H, t).

Example 2(7)

TLC: Rf 0.43 (hexane:ethyl acetate=2:1);

IR: ν 3436, 2936, 2862, 1556, 1467, 1443, 1418, 1390, 1337, 1257, 1211,1178, 1145, 1041, 837, 728, 656, 567 cm⁻¹;

NMR: δ 2.33–1.94 (3H, m), 1.67–1.18 (14H, m), 0.90 (3H, t).

Example 2(8)

TLC: Rf 0.36 (hexane:ethyl acetate=2:1);

IR (KBr): ν 3401, 2982, 2937, 1561, 1466, 1446, 1418, 1392, 1360, 1311,1257, 1209, 1153, 1097, 1041, 1017, 926, 846, 756, 656, 551, 422 cm⁻¹;

NMR: δ 2.30–1.90 (3H, m), 1.75–1.15 (8H, m), 0.91 (3H, t).

Example 2(9)

TLC: Rf 0.49 (hexane:ethyl acetate=2:1);

IR (KBr): ν 3431, 2937, 2863, 1639, 1554, 1460, 1443, 1415, 1390, 1319,1257, 1190, 1146, 1037, 838, 656 cm⁻¹;

NMR: δ 2.35–1.95 (3H, m), 1.70–1.10 (12H, m), 0.90 (3H, t).

Example 2(10)

TLC: Rf 0.36 (hexane:ethyl acetate=3:1);

IR (KBr): ν 3436, 2937, 2876, 1736, 1555, 1459, 1420, 1390, 1336, 1256,1200, 1148, 1083, 1026, 839, 656 cm⁻¹;

NMR: δ 2.30–1.95 (3H, m), 1.74–146 (10H, m), 0.90 (3H, t).

Example 2(11)–2(12)

The following compounds were obtained by the same procedure as a seriesof example 1→example 2, using the compound obtained in reference example7 or the compound obtained by the same procedure as a series ofreference example 5→reference example 6→reference example 7, using acorresponding compound.

Example 2(11)

TLC: Rf 0.40 (hexane:ethyl acetate=2:1);

IR (KBr): ν 3436, 2965, 2879, 1572, 1439, 1416, 1377, 1328, 1254, 1158,1117, 1083, 995, 957, 866, 830, 743, 660, 625, 592, 515 cm⁻¹;

NMR: δ 2.73–2.40 (2H, m), 2.25–1.94 (1H, m), 1.70–1.25 (4H, m), 0.92(3H, t).

Example 2(12)

TLC: Rf 0.22 (hexane:ethyl acetate=3:1);

IR (KBr): ν 3431, 2960, 2876, 1562, 1460, 1418, 1389, 1340, 1306, 1257,1227, 1155, 1099, 1051, 985, 907, 858, 572 cm⁻¹;

NMR: δ 2.30–1.90 (3H, m), 1.80–1.20 (6H, m), 0.92 (3H, t).

Example 3

To a solution of the compound of free acid obtained in example 2(8) (0.5g), oxalyl chloride (1.85 ml) was added at room temperature. The mixturewas stirred for 2 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure to give acyl chloride. A solution ofacyl chloride in ether (2 ml) was dropped to a solution of4-methoxyaniline (218 mg) and triethylamine (1 ml) in diethylether (10ml) at 0° C. The mixture was stirred for 1 hour. The reaction mixturewas washed with 2N hydrochloride, water and a saturated aqueous solutionof sodium chloride, successively, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was recrystallizedfrom a mixture of n-hexane and ethyl acetate (10:1) to give the titlecompound (412 mg) having the following physical data.

TLC: Rf 0.43 (hexane:ethyl acetate=2:1)

IR (KBr): ν 3449, 3243, 2951, 2870, 1655, 1603, 1546, 1515, 1459, 1445,1417, 1393, 1364, 1321, 1286, 1252, 1212, 1199, 1182, 1144, 1131, 1093,1036, 832, 741, 656, 558, 529, 430 cm⁻¹;

NMR (CDCl₃+CD₃OD): δ 7.46 (2H, d), 6.86 (2H, d), 3.80 (3H, s), 2.38–1.95(3H, m), 1.85 (8H, m), 0.92 (3H, t).

Example 3(1)–3(5)

The following compounds were obtained by the same procedure as a seriesof reaction of example 3 or example 3→example 1, using correspondingcompounds instead of 4-methoxyaniline in example 3.

Example 3(1)

TLC: Rf 0.63 (hexane:ethyl acetate=2:1)

IR (KBr): ν 3280, 3090, 2955, 2875, 1640, 1553, 1498, 1459, 1393, 1357,1286, 1255, 1220, 1206, 1155, 1136, 1098, 1045, 1027, 1004, 836, 743,693, 658, 580, 539, 491, 426 cm⁻¹;

NMR: δ 7.45–7.10 (5H, m), 5.90–5.60 (1H, br), 4.45 (2H, d), 2.20–1.853H, m), 1.80–1.10 (8H, m), 0.90 (3H, t).

Example 3(2)

TLC: Rf 0.38 (chloroform:methanol=10:1)

IR (KBr): ν 3293, 3253, 3189, 3133, 2955, 2875, 1660, 1603, 1547, 1484,1467, 1413, 1396, 1329, 1298, 1261, 1201, 1147, 1098, 1053, 1021, 942,887, 813, 747, 712, 636 cm⁻¹;

NMR: δ 8.56 (1H, d), 8.35 (1H, d), 8.21 (1H, dd), 7.61 (1H, s), 7.30(1H, dd), 2.35–1.90 (3H, m), 1.90–1.20 (8H, m), 0.93 (3H, t).

Example 3(3)

TLC: Rf 0.20 (chloroform:methanol=10:1)

[α]_(D) −25.39 (c=1.01, EtOH)

IR (KBr): ν 3293, 3089, 2940, 2878, 1719, 1646, 1547, 1466, 1397, 1377,1360, 1327, 1287, 1260, 1222, 1210, 1132, 1054, 1025, 946, 837, 659,592, 422 cm⁻¹;

NMR: δ 9.20–8.60 (1H, br), 6.40–6.00 (1H, br), 4.75–4.40 (1H, br),2.30–1.10 (11H, br), 1.00–0.85 (3H, br).

Example 3(4)

TLC: Rf 0.29 (chloroform:methanol=10:1)

IR (KBr): ν 3302, 2960, 2876, 2664, 1694, 1661, 1591, 1552, 1451, 1414,1359, 1288, 1257, 1194, 1148, 1093, 1050, 1016, 948, 911, 815, 756, 685,665, 665, 564 cm⁻¹;

NMR (CDCl₃+CD₃OD): δ 8.07 (1H, dd), 7.98 (1H, d), 7.78 (1H, dd), 7.41(1H, t), 2.42–1.90 (3H, m), 1.85–1.15 (8H, m), 0.93 (3H, t).

Example 3(5)

TLC: Rf 0.54 (hexane:ethyl acetate=5:1)

IR (KBr): ν 3031, 2960, 2875, 1733, 1498, 1456, 1392, 1256, 1210, 1148,748, 700 cm⁻¹;

NMR (CDCl3): δ 7.30–7.19 (5H, m), 4.32 (2H, t), 2.94 (2H, t), 2.40–2.25(1H, m), 2.10–1.85 (2H, m), 1.80–1.10 (8H, m), 0.86 (3H, t).

Reference Example 4

A solution of the compound obtained in reference example 1 (400 mg) inanhydrous dichloromethane (2 ml) was dropped to a solution of DAST (316μl) in anhydrous dichloromethane (2 ml) under an atmosphere of argon at−78° C. The mixture was stirred for 1.5 hours at 0° C. The reactionmixture was diluted with ether, washed with water and a saturatedaqueous solution of sodium chloride, successively, concentrated underreduced pressure. The residue was purified by column on silica gel(hexane:ethyl acetate=20:1) to give the title compound (132 mg) havingthe following physical data.

TLC: Rf 0.67 (hexane:ethyl acetate=3:1)

Example 4

To a solution of the compound obtained in reference example 4 (132 mg)in ethanol (2 ml), 10% palladium on carbon (10 mg) was added, under anatmosphere of argon. The mixture-was stirred vigorously for 2 hours atroom temperature under an atmosphere of hydrogen. The mixture wasfiltered through Celite and washed with ethyl acetate. The organic layerwas concentrated under reduced pressure to give the title compoundhaving the following physical data.

TLC: Rf 0.48 (hexane:ethyl acetate=10:1)

Example 5

To a solution of diisopropylamine (1.3 ml) in anhydrous tetrahydrofuran(10 ml), a solution of 1.6M n-butyllithium in hexane (4.6 ml) wasdropped, under an atmosphere of argon at 0° C. The mixture was stirredfor 30 minutes. To the reaction solution, a solution of ethyl phenylacetate (1.00 g) in tetrahydrofuran (3 ml) was dropped, at −78° C. Themixture was stirred for 40 minutes. To the reaction solution, a mixtureof a solution of 1-iodopropane (1.24 g) in tetrahydrofuran (2 ml) andhexamethyl phospholamide (2 ml) was dropped. The mixture was stirred for3 hours. The reaction mixture was diluted with ether, washed with asaturated aqueous solution of ammonium chloride, water and a saturatedaqueous solution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by column on silica gel (hexane ethyl acetate=40:1) to givethe title compound (788 mg) having the following physical data.

TLC: Rf 0.43 (hexane:ethyl acetate=20:1)

Example 6

To a solution of methyl 2-hydoxypentanoate (300 mg) in dimethylformamide(3 ml), sodium hydride (109 mg) was added, under an atmosphere of argonat 0° C. The mixture was stirred for 30 minutes at room temperature.1-Iodopropane (266 μl) was dropped to the reaction mixture. The mixturewas stirred for 8 hours. The reaction mixture was diluted with ether,washed with water and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by column on silica gel(hexane:ethyl acetate=30:1) to give the title compound (91 mg) havingthe following physical data.

TLC: Rf 0.75 (hexane:ethyl acetate=3:1)

Example 7

To a solution of the compound obtained in example 4 in ethanol (2 ml),5N aqueous solution of sodium hydroxide (0.5 ml) was added. The mixturewas stirred for 2 hours at 60° C. The reaction mixture was concentratedunder reduced pressure. The residue was acidified by adding 2Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with water and a saturated aqueous solution of sodiumchloride, successively, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by columnon silica gel (hexane:ethyl acetate=4:1–2:1) to give the compound offree acid (112 mg). To the above compound in ethanol (2 ml), 1 N aqueoussolution of sodium hydroxide (534 μl) was added. The mixture wasconcentrated under reduced pressure to give the title compound havingthe following physical data.

TLC: Rf 0.12 (hexane:ethyl acetate=4:1);

IR: ν 3368, 2934, 2862, 1557, 1455, 1417, 1318, 1044, 749 cm⁻¹;

NMR: δ 4.43 (2H, td), 2.23 (1H, m), 1.85–1.20 (12H, m), 0.94 (3H, t).

Example 7(1)–7(22)

The following compounds were obtained by the same procedure as a seriesof reaction of reference example 1→reference example 4→example 4→example7 or reference example 1→example 4→example 7, using a correspondingaldehyde.

Example 7(1)

TLC: Rf 0.38 (hexane:ethyl acetate=3:1);

NMR: δ 4.43 (2H, td), 2.23 (1H, m), 1.22–1.89 (14H, m), 0.95 (3H, t).

Example 7(2)

TLC: Rf 0.74 (hexane:ethyl acetate=2:1);

NMR: δ 4.43 (2H, td), 2.22 (1H, m), 1.20–1.85 (16H, m), 0.94 (3H, t).

Example 7(3)

TLC: Rf 0.33 (hexane:ethyl acetate=4:1);

NMR: δ 2.32 (1H, m), 1.97–1.80 (1H, br), 1.77–1.03 (14H, m), 1.00–0.70(5H, m).

Example 7(4)

TLC: Rf 0.29 (hexane:ethyl acetate=4:1);

NMR: δ 2.13 (1H, m), 1.80–1.05 (17H, m), 1.00–0.73 (5H, m).

Example 7(5)

TLC: Rf 0.35 (hexane:ethyl acetate=4:1);

NMR: δ 2.17 (1H, m), 1.78–1.05 (19H, m), 1.00–0.70 (5H, m).

Example 7(6)

TLC: Rf 0.32 (hexane:ethyl acetate=3:1);

NMR: δ 7.30–7.05 (5H, m), 3.00–2.85 (1H, m), 2.70–2.40 (2H, m),1.70–1.10 (4H, m), 0.87 (3H, t).

Example 7(7)

TLC: Rf 0.30 (hexane:ethyl acetate=4:1);

NMR: δ 7.30–7.00 (5H, m), 2.60 (2H, t), 2.21 (1H, m), 1.75–1.15 (8H, m),0.89 (3H, t).

Example 7(8)

TLC: Rf 0.31 (hexane:ethyl acetate=3:1);

NMR: δ 7.35–7.00 (5H, m), 2.58 (2H, t), 2.30–2.05 (1H, m), 1.80–1.10(10H, m), 0.89 (3H, t).

Example 7(9)

TLC: Rf 0.21 (hexane:ethyl acetate=5:1);

NMR: δ 7.20 (2H, m), 6.92 (3H, m), 3.99 (2H, m), 2.27 (1H, m), 1.31–1.89(8H, m), 0.95 (3H, m).

Example 7(10)

TLC: Rf 0.26 (hexane:ethyl acetate=3:1);

NMR: δ 3.55–3.35 (4H, m), 2.36–2.15 (1H, m), 1.95–1.23 (6H, m), 1.16(3H, t), 0.91 (3H, t).

Example 7(11)

TLC: Rf 0.16 (hexane:ethyl acetate=2:1);

NMR: δ 3.40 (2H, t), 3.29 (3H, s), 2.35–2.15 (1H, br), 1.92–1.20 (6H,m), 0.91 (3H, t).

Example 7(12)

TLC: Rf 0.32 (hexane:ethyl acetate=1:1);

NMR: δ 3.50–3.20 (5H, m), 2.30–2.05 (1H, br), 1.75–1.15 (8H, m), 0.90(3H, t).

Example 7(13)

TLC: Rf 0.41 (hexane:ethyl acetate=1:1);

NMR: δ 3.55–3.38 (4H, m), 2.30–2.08 (1H, m), 1.70–1.20 (8H, m), 1.16(3H, t), 0.90 (3H, t).

Example 7(14)

TLC: Rf 0.32 (hexane:ethyl acetate=1:1);

NMR: δ 3.45–3.30 (2H, m), 3.30 (3H, s), 2.30–2.05 (1H, m), 1.70–1.15(10H, m), 0.95–0.80 (3H, br).

Example 7(15)

TLC: Rf 0.22 (hexane:ethyl acetate=10:1);

NMR: δ 2.32 (1H, m), 1.02–1.74 (7H, m), 0.92 (9H, m).

Example 7(16)

TLC: Rf 0.38 (hexane:ethyl acetate=4:1);

NMR: δ 2.15 (1H, m), 1.70–1.10 (9H, m), 1.00–0.75 (9H, m).

Example 7(17)

TLC: Rf 0.34 (hexane:ethyl acetate=3:1);

NMR: δ 2.25–2.08 (1H, m), 1.65–1.05 (13H, m), 0.90 (3H, t), 0.87 (6H,d).

Example 7(18)

TLC: Rf 0.35 (hexane:ethyl acetate=3:1);

NMR: δ 2.30–2.05 (1H, m), 1.67–1.07 (11H, m), 0.90 (3H, t), 0.87 (6H,d).

Example 7(19)

TLC: Rf 0.34 (hexane:ethyl acetate=3:1);

NMR: δ 2.22–2.05 (1H, m), 1.65–1.05 (13H, m), 0.88 (3H, t), 0.85 (6H,t).

Example 7(20)

TLC: Rf 0.29 (hexane:ethyl acetate=5:1);

NMR: δ 2.20–2.00 (1H, br), 1.65–1.10 (8H, m), 0.95–0.80 (12H, m).

Example 7(21)

TLC: Rf 0.53 (hexane:ethyl acetate=3:1);

NMR: δ 2.24 (1H, m), 1.13–1.70 (10H, m), 0.92 (12H, m).

Example 7(22)

TLC: Rf 0.47 (chloroform:methanol=10:1);

NMR: δ 3.53 (2H, t), 2.28–2.10 (1H, m), 2.85–1.20 (12H, m), 0.90 (3H,t).

Example 7(23)–7(33)

The following compounds were obtained by the same procedure as inexample 7 using the compound obtained in example 5 or the compoundobtained by same procedure as in example 5 using a corresponding acetateinstead of ethyl phenyl acetate in example 5 or the compound obtained bythe same procedure as in example 5 using corresponding pentanoateinstead of ethyl phenyl acetate and corresponding compound instead of1-iodopropane in example 5, or by the same procedure as a series ofreaction of example 5→example 4→example 7, using a correspondingcarboxylate instead of ethyl phenyl acetate and 3-bromo-1-propen insteadof 1-iodopropane.

Example 7(23)

TLC: Rf 0.27 (hexane:ethyl acetate=1:1);

NMR: δ 7.40 (2H, m), 7.20 (3H, m), 3.45 (1H, m), 2.00 (1H, m), 1.65 (1H,m), 1.30 (2H, m), 0.95 (3H, t).

Example 7(24)

TLC: Rf 0.12 (hexane:ethyl acetate=1:1);

NMR: δ 7.20 (2H, m), 6.90 (3H, m), 4.35 (1H, m), 1.90 (2H, m), 1.55 (2H,m), 0.95 (3H, m).

Example 7(25)

TLC: Rf 0.24 (hexane:ethyl acetate=10:1);

NMR: 61.02–2.05 (14H, m), 0.92 (3H, t).

Example 7(26)

TLC: Rf 0.5 (hexane:ethyl acetate=3:1)

NMR: δ 1.00–2.04 (16H, m), 0.94 (3H, t).

Example 7(27)

TLC: Rf 0.56 (hexane:ethyl acetate=1:1);

NMR: δ 3.24 (1H, dd), 2.63 (1H, t), 2.60 (1H, t), 1.30–1.90 (10H, m),0.97 t), 0.94 (3H, t).

Example 7(28)

TLC: Rf 0.11 (hexane:ethyl acetate=10:1);

NMR: δ 5.85 (1H, m), 4.98 (2H, m), 2.00–2.50 (3H, m), 1.20–1.70 (4H, m),0.93 (3H, m).

Example 7(29)

TLC: Rf 0.29 (hexane:ethyl acetate=3:1);

NMR: δ 5.80 (1H, m), 5.03–4.90 (2H, m), 2.27–1.95 (3H, m), 1.65–1.15(10H, m), 0.89 (3H, t).

Example 7(30)

TLC: Rf 0.31 (hexane:ethyl acetate=5:1);

NMR: δ 2.19 (1H, m), 1.65–1.12 (12H, m), 0.90 (3H, t), 0.89 (3H, t).

Example 7(31)

TLC: Rf 0.37 (hexane:ethyl acetate=5:1);

NMR: δ 2.30–2.07 (1H, m), 1.65–1.10 (10H, m), 0.95–0.75 (6H, m).

Example 7(32)

TLC: Rf 0.31 (hexane:ethyl acetate=5:1);

NMR: δ 2.27–2.08 (1H, m), 1.65–1.15 (18H, m), 0.95–0.85 (6H, m).

Example 7(33)

TLC: Rf 0.50 (hexane:ethyl acetate=3:1);

NMR: δ 2.25 (1H, m), 1.20–1.70 (14H, m), 0.93 (6H, m).

Example 7(34)–7(38)

The following compounds were obtained by the same procedure as inexample 7 using the compound obtained in example 6 or the compoundobtained by the same procedure as in example 6 using a correspondingiodoalkane instead of 1-iodopropane in example 6.

Example 7(34)

TLC: Rf 0.11 (hexane:ethyl acetate=1:1);

NMR: δ 3.45–3.65 (2H, m), 3.71 (1H, td), 1.30–1.70 (6H, m), 0.91 (6H,t).

Example 7(35)

TLC: Rf 0.29 (hexane:ethyl acetate=10:1);

NMR: δ 3.64 (2H, m), 3.35 (1H, q), 1.72–1.25 (4H, m), 1.19 (3H, t), 0.92(3H, t).

Example 7(36)

TLC: Rf 0.5 (ethyl acetate)

NMR: δ 3.66 (2H, m), 3.28 (1H, m), 1.32–1.74 (8H, m), 0.96 (6H, t).

Example 7(37)

TLC: Rf 0.5 (ethyl acetate)

NMR: 3.66 (2H, m), 3.26 (1H, m), 1.30–1.76 (10H, m), 0.96 (6H, t).

Example 7(38)

TLC: Rf 0.12 (hexane:ethyl acetate=1:1);

NMR: δ 3.67 (2H, m), 3.30–3.15 (1H, m), 1.72–1.10 (12H, m), 0.98–0.83(6H, m).

Example 8

To a solution of 2-propyloctanoic acid (500 mg) in anhydrous benzene (5ml), oxalyl chloride (350 ml) was added at room temperature. The mixturewas stirred for 30 minutes at 50° C. The reaction mixture wasconcentrated under reduced pressure to give acyl chloride. A solution ofthe acyl chloride in tetrahydrofuran (3 ml) was dropped to a solution of50% dimethylamine (3 ml) at 0° C. The mixture was stirred 1 hour. Thereaction mixture was diluted with ether, washed with 2N hydrochloride,water and a saturated aqueous solution of sodium chloride, successively,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by column on silica gel (hexane:ethylacetate=2:1) to give the title compound (412 mg) having the followingphysical data.

TLC: Rf 0.43 (hexane:ethyl acetate=2:1);

IR: ν 2957, 2928, 2857, 1661, 1646, 1466, 1414, 1397, 1337, 1262, 1155,1111 cm⁻¹;

NMR (CDCl₃): δ 3.04 (3H, s), 2.96 (3H, s), 2.65 (1H, m), 1.10–1.85 (14H,m 0.87 (3H, t), 0.86 (3H, t).

Example 8(1)–8(6)

The following compounds were obtained by the same procedure as inexample 8 using a corresponding carboxylic acid and a correspondingamine.

Example 8(1)

TLC: Rf 0.19 (hexane:ethyl acetate=2:1)

NMR: 65.70–5.30 (1H, br), 2.81 (3H, d), 2.02 (1H, m), 1.80–1.10 (8H, m),0.89 (6H, t).

Example 8(2)

TLC: Rf 0.30 (hexane:ethyl acetate=2:1)

NMR: δ 3.06 (3H, s), 2.97 (3H, s), 2.68 (1H, m), 1.75–1.45 (2H, m),1.45–1.10 (6H, m), 0.89 (6H, t).

Example 8(3)

TLC: Rf 0.22 (hexane:ethyl acetate=2:1)

NMR (CDCl₃): δ 5.64 (1H, brs), 5.43 (1H, brs), 2.11 (1H, m), 1.10–1.80(14H, m), 0.90 (3H, t), 0.86 (3H, t).

Example 8(4)

TLC: Rf 0.64 (hexane:ethyl acetate=2:1); NMR (CDCl₃): δ 5.22 (1H, brd),4.10 (1H, m), 1.91 (1H, m), 1.18–1.75 (14H, m), 1.14 (6H, d), 0.88 (3H,t), 0.86 (3H, t).

Example 8(5)

TLC: Rf 0.41 (hexane:ethyl acetate=4:1)

NMR: δ 3.59 (2H, t), 3.49 (2H, t), 2.73–2.58 (1H, m), 1.75–1.45 (9H, m),1.45–1.10 (11H, m), 0.93–0.81 (6H, m).

Example 8(6)

TLC: Rf 0.20 (hexane:ethyl acetate=4:1)

NMR: δ 3.67 (4H, s), 3.68–3.60 (2H, m), 3.59–3.49 (2H, m), 2.69–2.52(1H, m), 1.74–1.51 (2H, m), 1.50–1.08 (12H, m), 0.93–0.80 (6H, m).

Example 9

To a solution of diisopropylamine (1.6 ml) in anhydrous THF (10 ml), 1.6M n-butyllithium in hexane (5.9 ml) was dropped under an atmosphere ofargon at 0° C. The mixture was stirred for 30 minutes. A solution ofmethyl 2-propylpentanoate (1.00 g) in THF (3 ml) was dropped to thereaction mixture at −78° C. The mixture was stirred for 15 minutes andthen 20 minutes. A solution of carbon tetrachloride (1.17 g) in THF (2ml) was added to the reaction mixture at −78° C. The mixture was stirredfor 80 minutes at room temperature. 1 N Hydrochloride was added to thereaction mixture. The mixture was diluted with ether, washed with waterand a saturated aqueous solution of sodium chloride, successively, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by column on silica gel (hexane:ethylacetate=40:1) to give the title compound (1.37 mg) having the followingphysical data.

TLC: Rf 0.45 (hexane:ethyl acetate=10:1);

NMR (CDCl₃): δ 3.76 (3H, s), 2.1–1.8 (4H, m), 1.6–1.1 (4H, m), 0.92 (6H,t).

Example 10

To a solution of the compound obtained in example 9 (600 mg) inanhydrous ether (10 ml), lithium aluminum hydride (119 mg) was added,under an atmosphere of argon at 0° C. The mixture was stirred for 30minutes. The reaction mixture was diluted with ether, washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by column on silica gel (hexane:ethyl acetate=10:1) to givethe 2-chloro-2-propylpentanol. To a solution of the above compound inanhydrous dichloromethane (14 ml), 4A molecular sieves (1.5 g) andpyridinium dichromate (1.29 g) was added, under an atmosphere of argon.The mixture was stirred for 3 hours at room temperature. The reactionmixture was diluted with ether, filtrated by silica gel. The filtrationwas concentrated under reduced pressure. The residue was purified bycolumn on silica gel (hexane:ethyl acetate=40:1). To a solution of theobtained aldehyde compound in t-butanol (3 ml), 2-methyl-2-butene (0.2ml) was added. And then an aqueous solution of sodium chlorite (248 mg)and sodium phosphate monobasic dihydrate (215 mg) in water (1 ml) wasadded to the mixture. The mixture was stirred for 30 minutes at roomtemperature. The reaction mixture was diluted with ethyl acetate, washedwater and a saturated aqueous solution of sodium chloride, successively,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by column on silica gel (hexane:ethylacetate=1:1) to give the compound of free acid (150 mg). To the abovecompound in ethanol (3 ml), 1N aqueous solution of sodium hydroxide (800ml) was added. The mixture was concentrated under reduced pressure togive the title compound (134 mg) having the following physical data.

TLC: Rf 0.11 (hexane:ethyl acetate=10:1)

IR (KBr): ν 3449, 2963, 2876, 1600, 1433, 1402, 1132, 763, 665 cm⁻¹;

NMR: 61.28–2.14 (8H, m), 0.95 (6H, t).

Example 11

(±)-2-Ethylhexanoic acid (5 g) being on the market and quinine (5.6 g)were dissolved under heating into 50% water contained acetone. Themixture was allowed to stand over night. The precipitated crystals wasfiltered. The crude crystals was dried under pressure, andrecrystallized from aqueous acetone (6 times). The crystals weredissolved into diluted hydrochloric acid, extracted with ether. Theorganic layer was washed water and a saturated aqueous solution ofsodium chloride, successively, dried and concentrated under reducedpressure to give the title compound (190 mg) having the followingphysical data.

[α]_(D) −8.7° (c=2.59, CHCl₃);

IR: ν 2964, 2876, 1708, 1461, 1290, 1231 cm⁻¹.

Reference Example 8

A solution of lithium diisopropylamide in heptane-tetrahydrofuran-ethylbenzene (2M, 5 ml) was added to tetrahydrofuran (THF) (5 ml) under anatmosphere of argon. The mixture was cooled at −70° C. A solution ofmethyl pentanoate (1.33 ml) in THF (3 ml) was added to the abovesolution. The mixture was stirred for 30 minutes at −70° C. A solutionof propanal (0.72 ml) in THF (3 ml) was dropped to the reaction mixture.The mixture was stirred for 15 minutes at −70° C. To the reactionmixture, a saturated aqueous solution of ammonium chloride was added.The mixture was extracted with ethyl acetate. The organic layer waswashed water and a saturated aqueous solution of sodium chloride,successively, dried and concentrated under reduced pressure. The residuewas purified by column on silica gel (hexane:ethyl acetate=9:1) to givethe hydroxy compound (752 mg). To a solution of the above compound (550mg) in methylene chloride (10 ml), triethylamine (0.57 ml) was added,under an atmosphere of argon. The mixture was cooled at −20° C. Asolution of mesyl chloride (0.29 ml) was dropped to the above solution.The mixture was stirred for 30 minutes at −20° C.–−10° C. The reactionmixture was poured into water with ice, and extracted with ethylacetate. The extract was washed with a saturated aqueous solution ofsodium chloride, dried and concentrated under reduced pressure to givethe title compound. The title compound was used the next reactionwithout a purification process.

Example 12

To a solution of the compound obtained in reference example 8 in benzene(10 ml), DBU (0.56 ml) was added, and stirred for 16 hours at room acid,and extracted with ethyl-acetate. The extract was washed water and asaturated aqueous solution of sodium chloride, successively, dried andconcentrated under reduced pressure. The residue was purified by columnon silica gel (hexane:ethyl acetate=20:1) to give the title compound(164 mg) and EZ mixture (114 mg).

Example 13

To the E compound obtained in example 12 (160 mg), 1N aqueous solutionof sodium hydroxide was added. The mixture was stirred for 1 hour atroom temperature, and for 1 hour at 50° C., and then for 12 hours atroom temperature. The reaction solution was diluted with ether. Waterwas added to the above solution. The solution was separated. The waterlayer was acidified by 1N hydrochloric acid, extracted with ethylacetate. The extract was washed water and a saturated aqueous solutionof sodium chloride, successively, dried and concentrated under reducedpressure. The residue was purified by column on silica gel (hexane:ethylacetate=10:1–2:1) to give the compound of free acid (117 mg). To theabove compound in dioxane, 1 N aqueous solution of sodium hydroxide wasadded. The mixture was freeze-dried to give the title compound havingthe following physical data.

TLC: Rf 0.22 (hexane:ethyl acetate=3:1)

IR (KBr): ν 3436, 2962, 2933, 2872, 1649, 1558, 1461, 1411, 1111 849,798 cm⁻¹.

Formulation Example 1

Preparation of Tablets

The following compounds were admixed in conventional method and punchedout to obtain 100 tablets each containing 100 mg of active ingredient.

sodium 5,5,5-trifluoro-2-propylpentanoate 10 g Cellulose calciumglycolate (disintegrating agent) 200 mg Magnesium stearate (lubricatingagent) 100 mg Micro crystalline cellulose 9.7 g

Formulation Example 2

Preparation of Tablets

The following compounds were admixed in conventional method and punchedout to obtain 100 tablets each containing 100 mg of active ingredient.

sodium 2-propylpentanoate 10 g Cellulose calcium glycolate(disintegrating agent) 200 mg Magnesium stearate (lubricating agent) 100mg Micro crystalline cellulose 9.7 g

BRIEF DESCRIPTION OF FIGURE

FIG. 1 was indicated an effect on brain ischemia of sodium valproate.

1. A compound of the formula (I):

wherein R¹ is C1–10 alkyl having one carbon substituted by 1–3fluorines; R² is hydroxy, C1–4 alkoxy, C1–4 alkoxy substituted by 1 ofphenyl, or NR³R⁴, in which R³ and R⁴ each, independently, is (i)hydrogen, (ii) C1–4 alkyl, (iii) phenyl, (iv) phenyl substituted by C1–4alkoxy or carboxyl, (v) 4–7 membered heterocyclic ring containing onenitrogen or (vi) C1–4 alkyl substituted by phenyl, phenyl substituted byC1–4 alkoxy or carboxyl, or 4–7 membered heterocyclic ring containingone nitrogen, or the nitrogen atom bonded to them, taken together is 4–7membered saturated heterocyclic ring containing one or two nitrogen(s)or one nitrogen and one oxygen, or amino acid residue; with the provisothat, R¹ is not F—(CH₂)₄—, F—(CH₂)₅—, F—(CH₂)₆—, F₃C—CH₂—, or non-toxicsalts thereof or acid addition salts thereof.
 2. A compound according toclaim 1, wherein R¹ is C1–7 alkyl having one carbon substituted by 1–3of fluorines.
 3. A compound according to claim 1, wherein R² is hydroxy,C1–4 alkoxy, C1–4 alkoxy substituted by 1 of phenyl.
 4. A compoundaccording to claim 1, wherein R² is NR³R⁴, in which R³ and R⁴ each,independently, is (i) hydrogen, (ii) C1–4 alkyl, (iii) phenyl, (iv)phenyl substituted by C1–4 alkoxy or carboxyl, (v) 4–7 memberedheterocyclic ring containing one nitrogen or (vi) C1–4 alkyl substitutedby phenyl, phenyl substituted by C1–4 alkoxy or carboxyl, or 4–7membered heterocyclic ring containing one nitrogen.
 5. A compoundaccording to claim 1, wherein R² is NR³R⁴, in which R³, R⁴ and thenitrogen atom bonded to them, taken together is 4–7 membered saturatedheterocyclic ring containing one or two nitrogens or one nitrogen andone oxygen, or amino acid residue.
 6. A compound according to claim 1,which is 5-fluoro-2-propylpentanoic acid, 6-fluoro-2-propylhexanoicacid, 5,5-difluoro-2-propylpentanoic acid,7,7-difluoro-2-propylheptanoic acid, 8,8-difluoro-2-propyloctanoic acid,6,6-difluoro-2-propylhexanoic acid, 9,9-difluoro-2-propylnonanoic acid,6,6,6-trifluoro-2-propylhexanoic acid, 8,8,8-trifluoro-2-propyloctanoicacid, 7,7,7-trifluoro-2-propylheptanoic acid,9,9,9-trifluoro-2-propylnonanoic acid, 4,4,4-trifluoro-2-propylbutanoicacid, 2-phenylethyl 6,6,6-trifluoro-2-propylhexanoate.
 7. A compoundaccording to claim 1, which is6,6,6-trifluoro-2-propyl-N-(4-methoxyphenyl)hexanamide,6,6,6-trifluoro-2-propyl-N-benzylhexanamide,6,6,6-trifluoro-2-propyl-N-(3-pyridyl)hexanamide,6,6,6-trifluoro-2-propyl-N-(3-carboxyphenyl)hexanamide.
 8. A compoundaccording to claim 1, which isN-(1-carboxyethyl)-6,6,6-trifluoro-2-propylhexamide.
 9. A pharmaceuticalcomposition which comprises, as active ingredient, an effective amountof a pentanoic acid derivative of the formula (I) depicted in claim 1 ornon-toxic salts thereof or acid addition salts thereof with apharmaceutical carrier or coating.